Endothelin in atherosclerosis: importance of risk factors and therapeutic implications.

Endothelin (ET)-1, a potent vasoconstrictor peptide, is primarily released abluminally from endothelial cells and exerts its biological effect through the activation of specific ET receptors. Endothelin subtype A receptors (ET(A)) are involved in constriction and proliferation of vascular smooth muscle cells, whereas endothelin subtype B receptors (ET(B)) on endothelial cells mediate the formation of nitric oxide, which acts as vasodilator and inhibits platelet aggregation. Cardiovascular risk factors such as hypertension and aging, as well as hypercholesterolemia, which are precursors of atherosclerosis, and elevated ET-1 levels are found. The best approach to determine the contribution of endogenous ET to vascular structural and functional alterations can be achieved by chronic inhibition of ET receptors with ET receptor antagonists. Recent studies showed favourable effects of selective ET(A)-antagonists on vascular alterations in different experimental models of hypertension, hypercholesterolemia and atherosclerosis, suggesting that activation of the local ET system importantly contributes to endothelial dysfunction and vascular remodeling, mainly through ET(A) receptors. Chronic blockade of ET(A) receptors may be a new therapeutic approach for the treatment of atherosclerosis and its risk factors.